Clinical Trial Management & Part 11 Compliance
Clinical Trial Management Background What is Good Clinical Practice?
Clinical Trial Management A process enabling reliable decisions about allowing a medical product to be marketed
Product Approval Factors
Product is safe
Treatment is effective for disease or condition it is meant to treat
Clinical Research Project Principles
Control bias in subject selection
Compensate for placebo effect
Reduce examiner bias
Objectively compare results to other treatments or controls
Produce sufficient statistical power
The Study Protocol
Explains problem & proposes treatment hypothesis
Describes key variables to assess safety & efficacy
Specifies & justifies study sample size
Describes study population
The Study Protocol
Identifies exams and allowable measurement intervals
Specifies clinical and data endpoints
Explains how data collected will be analyzed
Protocol Implementation
Qualified study sites
Appropriate equipment & instrumentation
Adequate training of study team
Appropriate data collection instruments
Adequate data storage mechanism
Adequate study monitoring
Monitoring Study Progress
Subject enrollment
Subject accountability at study exams
Data recorded & collected
Standard Study Data Documents
Source documents
Data capture forms (CRFs)
Data query forms
Source Document
Initial capture of clinical history data, impressions,
diagnoses and plans of care
Hospital records
Clinic/office charts
Lab reports
Subject Diaries
Required to substantiate data submitted to
sponsor via CRFs
Data Capture Forms
Case Report Form (CRF)
Electronic Data Capture (e-CRF)
Case Report Form Completion
Formally authorized staff for CRF entries
Complete all fields in (black) ink
No unnecessary marks or notations
Data changes must not obliterate original entry
Changes must be initialed and dated
Investigator signs CRFs after finalization
Data Flow at Site
Site sees subject, records exam data on source doc
Site transcribes source data to CRF
Study monitor verifies data capture & submits to sponsor
Data Flow at Sponsor/CRO
Sponsor/CRO enters data to database (#1)
Sponsor/CRO enters data to database (#2) – “verifies”
Sponsor/CRO visually reviews CRF data/logic checks
Data Query Forms
After CRFs reviewed by sponsor/CRO, further verification or clarification may be required
Provide traceability regarding data changes
Data Queries
Data queries generated by sponsor/CRO for resolution by site
Formally authorized staff for query responses
Completed queries must be signed by investigator or authorized staff
Copy of completed data queries filed at site
Query records in sponsor’s permanent database
Data Query Flow
Sponsor/CRO visually reviews CRF data/logic checks
Sponsor/CRO generates data query form & sends
Site responds to query & returns
Sponsor/CRO revises database entry as necessary
General Principles System Definitions
Protocol should identify when computerized system is used
Documentation should identify hardware & software used
General Principles Source Documents
Retain to reconstruct & evaluate trial
Investigators retain originals or certified copies
When original observations entered directly, e-record is “source”
General Principles Data Accountability
All info for each subject attributable to that subject
Record changes shouldn’t obscure original info
Record changes should be indicated & means provided to check prior entry
Necessity of audit trail – who changed & why?
General Principles Thoughtful System Design
Matches data capture requirements (kg. vs. lb.)
Precludes errors in modification, maintenance, archiving, retrieval or transmission
Ensures record keeping & retention are in-line with paper systems
General Principles Security Measures
To prevent unauthorized access to data
To prevent unauthorized access to computerized system
General Principles FDA Records Access
May inspect all records intended to support submissions
e-Data Flow at Site
Site sees subject, records exam data on source doc
Site inputs data to computer & “commits”
e-Data Flow at Sponsor/CRO
Study monitor visually reviews “committed” data vs. “source”
Sponsor/CRO reviews CRF data/applies logic checks
Additional Site Qualification Questions
Previous experience/comfort level with e-data collection activities?
Computer/high-speed internet accessibility?
On-site technical support capabilities?
Additional Site Management Planning
Site & subject training and documentation for e-data capture
Ongoing monitor communication & support
Technical “Help Desk”
E-signature management
Add’l Systems Design Issues Data Entry
Prompts for clinical terms & measurements
Prompts for out of range data
Electronic diaries & e-CRFs designed to allow annotations
Features to facilitate data review & identify changes
Sponsor access to data during study
Add’l Systems Design Issues Electronic Signatures
Individual enters signature at start of data entry session
Attributability of signatures
Passwords changed at established intervals
Add’l Systems Design Issues Date/Time Stamps
Controls to ensure correct system date/time (yr, mo, day, hr, min)
Limited ability (with documentation) to change date/time
Add’l Systems Design Issues Controls
SOPs to maintain system integrity in light of changes
Revalidation for changes exceeding operation limits/design specs
Documentation of software versions
SOPs for contingency plans
SOPs for backup & recovery of e-records
Logs to assess nature & scope of data loss in the event of system failure
Secure storage of backup records
Consider Speed of Data Capture vs. Costs Incurred
Clinical Project Planning
Skilled, regularly available technical support
Detailed hazard/failure analyses
Skilled, regularly available monitoring/training support
Increased budget for site participation
Adequate schedule “padding” for things to go wrong